Selective activation of ?7 nicotinic acetylcholine receptor by PHA-543613 improves A?25-35-mediated cognitive deficits in mice.

Abstract

Agonists of ?7 nicotinic acetylcholine receptors (nAChRs) are currently being considered as therapeutic approaches for managing cognitive deficits in Alzheimer's disease (AD). Present study was designed to evaluate the effect of ?7 nAChR selective activation by PHA-543613 (PHA) on beta-amyloid (A?)25-35-mediated cognitive deficits in mice. For this purpose, PHA (1mg/kg, i.p.), a selective ?7 nAChR agonist, and galantamine (Gal) (3mg/kg, s.c.), an acetylcholine-esterase inhibitor (AChEI) effects on ?7 nAChR were tested in A?25-35-received (intracerebroventricular, 10 nmol) mice model of AD. Methyllycaconitine (MLA) (1mg/kg, i.p.), a ?7 nAChR antagonist, was used for receptor blockage effects evaluation. Working and reference memory in animals was assessed by the Morris water maze (MWM) task. The mRNA and protein levels of ?7 subunit were analyzed by real-time PCR and Western blotting, respectively. PHA and Gal, ameliorate A?-impaired working and reference memory. However, Gal had less effect than PHA in this regard. Pretreatment with MLA reverses both Gal and PHA effects in MWM. PHA and Gal treatment prevent A?-induced ?7 subunit protein reduction, but Gal has lesser effect than PHA. This effect blocked by pretreatment with MLA. In neither the pretreatment nor treatment group, the mRNA levels of nAChR ?7 subunit were significantly changed. Therefore, ?7 nAChR activation, reduces A?-induced cognitive deficits and increases the ?7 protein level and subsequent neuron survival. However, blockage of receptor, increases A? toxicity and cognitive impairment and reduces the ?7 nAChR protein level and flowing neuroprotection.